Rocaglaol derivatives as cardioprotectant agents and as antineoplastic agents

Abstract

The present invention discloses new rocaglaol derivatives and the use of rocaglaol derivatives to prevent or to limit the cardiotoxicity of an antineoplastic agent, in particular to prevent or to limit the apoptosis of cardiomyocytes induced by such agent.

1 - 34 . (canceled) 
     
     
         35 . A method for preventing or limiting the cardiotoxicity of an antineoplastic agent in a subject comprising administering to said subject a therapeutically effective amount of a rocaglaol derivative of the formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         R 11  is alkoxy, optionally substituted; 
         R 12  is hydrogen; 
         or R 11  and R 12  together form a —O—CH 2 —O-unit; 
         R 13  is selected from the group consisting of hydrogen and (C 1 -C 3 )-alkoxy; 
         R 14  is selected from the group consisting of hydroxyl, oxo group, and —OCOR 20 , R 20  being selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl, ═N—OR 26  with R 26  being H or methyl, —NH—(CH 2 ) m —R 27 , wherein m is 0 or 1 and R 27  is selected from the group consisting of H, —OH, —SO 2 Me, and —COR 28  with R 28  being H or (C 1 -C 3 )-alkyl; 
         R 15  is selected from the group consisting of hydrogen, —COOR 21 , —CONR 22 R 23  and —CONH(CH 2 ) n OH, wherein n is 2, 3 or 4, wherein 
         R 21  and R 23  are independently selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl and R 22  is selected from the group consisting of (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkyl and hydrogen, or R 22  and R 23  together form a 5 atom heterocycle, optionally substituted by a group NHCO—(C 1 -C 4 )-alkyl; 
         or R 14 , R 15  and carbons (α) and (β) bearing R 14  and R 15  together form 
       
       
         
           
           
               
               
           
         
         wherein R 24  and R 25  are independently selected from the group consisting of (C 1 -C 3 )-alkyl and hydrogen; 
         R 16  is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkoxy and halogen; 
         R 17  is in ortho-position to R 16  and is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkoxy and hydroxyl or form together with R 17  a —O—CH 2 —O-unit; and 
         R 18  and R 19  are independently selected from the group consisting of hydrogen and halogen; 
         or any pharmaceutically acceptable salt thereof. 
       
     
     
         36 . The method according to  claim 35 , wherein the rocaglaol derivative of the formula (II) has one or several of the following features:
 a) R 12  is H and R 11  is selected from the group consisting of methoxy and ethoxy;   b) R 13  is selected from the group consisting of hydrogen, methoxy and ethoxy;   c) R 14  is selected from the group consisting of hydroxyl and —OCOR 20 , R 20  being selected from the group consisting of hydrogen, methyl and ethyl, —NH—(CH 2 ) m —R 27 , wherein m is 0 and R 27  is —SO 2 Me or —COR 28  with R 28  being H or (C 1 -C 3 )-alkyl;   d) R 15  is selected from the group consisting of hydrogen, —COOR 21 , and —CONR 22 R 23 , wherein R 21  and R 23  are independently selected from the group consisting of hydrogen and methyl, and R 22  is selected from the group consisting of hydrogen, methyl and methoxy;   e) R 16  is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkoxy and halogen;   f) R 17  is hydrogen; and   g) R 18  is in para and is H or fluorine and R 19  is hydrogen.   
     
     
         37 . The method according to  claim 35 , wherein the rocaglaol derivative presents the formula (IIa) or (IIb) 
       
         
           
           
               
               
           
         
         wherein the definition of R11, R12, R13, R14, R15, R16, R17, R18 and R19 is the same as in  claim 35 . 
       
     
     
         38 . The method according to  claim 35 , wherein the rocaglaol derivative has the formula (IIa) and R 14  is selected from the group consisting of hydroxyl and —OCOR 20 , R 20  being selected from the group consisting of hydrogen and hydrogen, methyl and ethyl, and ═N—OR 26  with R 26  being H or methyl. 
     
     
         39 . The method according to  claim 37 , wherein the rocaglaol derivative has the formula (IIb) and R 14  is —NH—(CH 2 ) m —R 27 , wherein m is 0 and R 27  is —SO 2 Me or —COR 28  with R 28  being H or (C 1 -C 3 )-alkyl. 
     
     
         40 . The method according to  claim 35 , wherein the rocaglaol derivative is selected from the group consisting of FL1, FL3, FL5, FL6, FL7, FL8, FL9, FL10, FL12, FL13, FL14, FL15, FL16, FL17, FL18, FL19, FL20, FL21, FL22, FL23, FL24 and FL25. 
     
     
         41 . A rocaglaol derivative of the formula (I) 
       
         
           
           
               
               
           
         
         wherein
 R 3  is —CONH 2 ; 
 and wherein
 R 1  is alkoxy, optionally substituted; 
 R 2  is selected from the group consisting of hydrogen and (C 1 -C 3 )-alkoxy; and 
 R 4  is halogen, 
 
 or,
 R 1  is alkoxy, optionally substituted; 
 R 2  is hydrogen; and 
 R 4  is selected from the group consisting of hydrogen and alkoxy, 
 
 or,
 R 1  is a substituted alkoxy; 
 R 2  is (C 1 -C 3 )-alkoxy; and 
 R 4  is selected from the group consisting of hydrogen and alkoxy, 
 
 
         or wherein
 R 3  is —COOR 5  wherein R 5  is (C 1 -C 3 )-alkyl; 
 R 1  is alkoxy, optionally substituted; 
 R 2  is hydrogen; and 
 R 4  is selected from the group consisting of hydrogen, methoxy and halogen; 
 
         or wherein
 R 1  is methoxy, and R 4  is bromine, 
 and wherein
 R 2  is (C 1 -C 3 )-alkoxy, and 
 R 3  is hydrogen, 
 
 or
 R 2  is hydrogen, and 
 R 3  is selected from the group consisting of hydrogen, —COOR 5  and —CONR 6 R 7 , wherein 
 R 5  is (C 1 -C 3 )-alkyl and R 6  and R 7  are independently selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl; 
 
 
         or any pharmaceutically acceptable salt thereof. 
       
     
     
         42 . The rocaglaol derivative according to  claim 41 , wherein the rocaglaol derivative is selected from the group consisting of FL3, FL5, FL6, FL7, FL5, FL9 and FL14. 
     
     
         43 . A rocaglaol derivative of the formula (II) 
       
         
           
           
               
               
           
         
         wherein 
         R 11  is alkoxy, optionally substituted; 
         R 12  is hydrogen; 
         or R 11  and R 12  together form a —O—CH 2 —O-unit; 
         R 13  is selected from the group consisting of hydrogen and (C 1 -C 3 )-alkoxy; 
         R 14  is —NH—R 27 , wherein R 27  is selected from the group consisting of —SO 2 Me and —COR 28  with R 28  being H or (C 1 -C 3 )-alkyl; 
         R 15  is selected from the group consisting of hydrogen, —COOR 21 , —CONR 22 R 23  and —CONH(CH 2 ) n OH, wherein n is 2, 3 or 4, wherein
 R 21  and R 23  are independently selected from the group consisting of hydrogen and (C 1 -C 3 )-alkyl and R 22  is selected from the group consisting of (C 1 -C 3 )-alkoxy, (C 1 -C 3 )-alkyl and hydrogen, or 
 R 22  and R 23  together form a 5 atom heterocycle, optionally substituted by a group NHCO—(C 1 -C 4 )-alkyl; 
 
         R 16  is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkoxy and halogen; 
         R 17  is in ortho-position to R 16  and is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkoxy and hydroxyl or form together with R 17  a —O—CH 2 —O-unit; and 
         R 18  and R 19  are independently selected from the group consisting of hydrogen and halogen; 
       
       or any pharmaceutically acceptable salt thereof. 
     
     
         44 . The rocaglaol derivative according to  claim 43 , wherein the rocaglaol derivative of the formula (II) has one or several of the following features:
 a) R 11  is alkoxy and R 12  is hydrogen;   b) R 13  is selected from the group consisting of hydrogen and methoxy;   c) R 14  is —NH—R 27 , wherein R 27  is selected from the group consisting of —SO 2 Me and —COR 28  with R 28  being H, methyl or ethyl;   d) R 15  is selected from the group consisting of hydrogen, —COOR 21 , and —CONR 22 R 23 , wherein R 21  and R 23  are independently selected from the group consisting of hydrogen and methyl, and R 22  is selected from the group consisting of hydrogen, methyl and methoxy;   e) R 16  is selected from the group consisting of hydrogen, (C 1 -C 3 )-alkoxy and halogen;   f) R 17  is hydrogen; and   g) R 18  is in para and is H or fluorine and R 19  is hydrogen.   
     
     
         45 . The rocaglaol derivative according to  claim 43 , wherein the rocaglaol derivative presents the formula (IIa) or (IIb) 
       
         
           
           
               
               
           
         
         wherein the definition of R11, R12, R13, R14, R15, R16, R17, R18 and R19 is the same as in  claim 43 . 
       
     
     
         46 . The rocaglaol derivative according to  claim 45 , wherein the rocaglaol derivative has the formula (IIb) and R 14  is —NH—R 27 , wherein R 27  is —SO 2 Me or —COR 28  with R 28  being H or (C 1 -C 3 )-alkyl. 
     
     
         47 . The rocaglaol derivative according to  claim 43 , wherein the rocaglaol derivative is selected from the group consisting of FL22, FL23, FL24 and FL25. 
     
     
         48 . A rocaglaol derivative of the formula (IIa) 
       
         
           
           
               
               
           
         
         wherein 
         R 12  is H and R 11  is selected from the group consisting of methoxy and ethoxy; 
         R 13  is selected from the group consisting of hydrogen, methoxy and ethoxy; 
         R 14  is —OCOR 20 , R 20  being selected from the group consisting of hydrogen, methyl and ethyl; 
         R 15  is selected from the group consisting of hydrogen, —COOR 21 , and —CONR 22 R 23 , wherein R 21  and R 23  are independently selected from the group consisting of hydrogen and methyl, and R 22  is selected from the group consisting of hydrogen, methyl and methoxy; R 16  is selected from the group consisting of chlorine, bromine and fluorine; 
         R 17  is hydrogen; and 
         R 18  is in para and is H or fluorine and R 19  is hydrogen; 
         or any pharmaceutically acceptable salt thereof. 
       
     
     
         49 . The rocaglaol derivative according to  claim 48 , wherein the rocaglaol derivative is selected from the group consisting of FL19, FL20 and FL21. 
     
     
         50 . A rocaglaol derivative of the formula (IIa) 
       
         
           
           
               
               
           
         
         wherein 
         R 12  is H and R 11  is selected from the group consisting of methoxy and ethoxy; 
         R 13  is selected from the group consisting of hydrogen, methoxy and ethoxy; 
         R 14  is hydroxyl; 
         R 18  is in para and is fluorine and R 19  is hydrogen, 
         and wherein
 R 15  is selected from the group consisting of hydrogen, —COOR 21 , and —CONR 22 R 23 , wherein 
 R 21  and R 23  are independently selected from the group consisting of hydrogen and methyl, and R 22  is selected from the group consisting of hydrogen, methyl and methoxy; and 
 R 16  is bromine and R 17  is hydrogen; 
 
         or
 R 15  is selected from the group consisting of —COOR 21 , and —CONR 22 R 23 , wherein R 21  and R 23  are independently selected from the group consisting of hydrogen and methyl, and R 22  is selected from the group consisting of hydrogen, methyl and methoxy; and 
 R 16  is methoxy and R 17  is hydrogen; 
 
         or any pharmaceutically acceptable salt thereof. 
       
     
     
         51 . The rocaglaol derivative according to  claim 50 , wherein the rocaglaol derivative is FL16, FL17 or FL18. 
     
     
         52 . A pharmaceutical composition comprising a rocaglaol derivative according to  claim 41  and a pharmaceutically acceptable carrier and/or excipient. 
     
     
         53 . A pharmaceutical composition comprising a rocaglaol derivative according to  claim 43  and a pharmaceutically acceptable carrier and/or excipient. 
     
     
         54 . A pharmaceutical composition comprising a rocaglaol derivative according to  claim 48  and a pharmaceutically acceptable carrier and/or excipient. 
     
     
         55 . A pharmaceutical composition comprising a rocaglaol derivative according to  claim 50  and a pharmaceutically acceptable carrier and/or excipient.